DESCRIPTION Recent in vitro studies have suggested that toxic effects of cadmium on endothelial cells may involve reactive oxidant generation. In addition, cadmium rapidly induces expression of metallothionein in these cells, which may protect against cadmium-induced injury through antioxidant effects. One interpretation of these findings is that cadmium-induced endothelial oxidant generation may be a critical event in the development of microvascular injury and subsequent organ damage. The specific aims of this proposal are to: 1) establish, using intravital microscopy, the magnitude and time-course of microvascular injury following cadmium exposure (as evidenced by leukocyte adhesion, increased venular permeability to plasma protein, and increased sensitivity of venular endothelial cells to laser-induced injury); 2) evaluate the role of reactive oxidants in cadmium-induced microvascular dysfunction (as evidenced by attenuation by antioxidants and in MT-transgenic mice, augmentation in MT knock-out mice, increased endothelial metallothionein, and increases in nitric oxide, endothelin-I, and plasma TBARS); and 3) determine whether reactive oxidant generation during chronic cadmium exposure augments the severity of microvascular injury during hemorrhagic shock, sepsis, or diabetes. The proposed studies will utilize intravital microscopy to directly examine microvascular alterations in the cremaster muscle and liver. The central goal is to evaluate the role of oxidant generation in the development of microcirculatory impairment and enhanced cardiovascular disease following exposure to cadmium.